The present invention concerns the condensation of methylbenzoxazole derivatives with aromatic aldehyde derivatives in the presence of strong base at low temperature, followed by warming, to give compounds of formula III. ##STR1##
Related compounds are medicinally important enzyme inhibitors, most notably H.sup.+ K.sup.+ -ATPase inhibitors to reduce gastric acid secretion. Simple hydrogenation of pyridinones of III yields compounds which possess HIV reverse transcriptase inhibitory activity.
The synthesis of formula III compounds (hereinafter "styrylbenzoxazoles") occurs via condensation of aromatic aldehydes with methylbenzoxazoles, perhaps by deprotonation of methylbenzoxazole prior to condensation with the aldehyde. In the prior art, related condensations were accomplished under extreme experimental conditions. For example, condensation of benzaldehyde with 2-methylbenzoxazole using potassium methoxide as the catalyst required refluxing of the reaction for 7 hours. This condensation was also achieved using boric acid as the catalyst when the reaction was incubated at about 200.degree. C. when zinc chloride or acetic anhydride was used as the catalyst. In addition to being unsuitable for large scale preparation of products, these condensations afford low to moderate yields of product.
Lokande and Rangnekar developed a more convenient method for the synthesis of styrylbenzoxazoles via condensation of aryl aldehydes with methylbenzoxazole [Ind. J. Chem. 25B, 485 (1986)]. This method employs the use of phase-transfer catalysis by aqueous sodium hydroxide and affords milder reaction conditions, shorter reaction periods and higher yields of styryl product than the previous methodology. This method has features which make it impractical for large scale preparations of styryl products. First, the process is performed in the absence of solvent, and its reaction mixtures are not useful for large scale synthesis. Secondly, the use of phase transfer catalysis affords products of higher impurity than is pharmacologically acceptable. Removal of impurities is expensive and laborious.
More recently, the deprotonation of methylbenzoxazole was accomplished using butyllithium as the catalyst at a temperature of -100.degree. C. [Epifani, E. et al. Tetrah. Lett. 28, 6385 (1987)]. In addition to being operationally difficult on a large scale, the process results in recovery of only the intermediate alcohol adduct. An extra elimination step is required to achieve the desired olefin product. Use of butyllithium methodology is also described in EPO 462800 (e.g. Example 4, Step G).
The existing methodology for the condensation of aldehydes and benzoxazoles has several disadvantages. In addition to requiring operationally difficult temperatures, these methods afford low or modest yields of the olefin product. The prior methods also yield impurities which are expensive to remove. Thus a new direct route to the synthesis of.styrylbenzoxazoles of acceptable pharmacological purity would be superior to existing methodology.
The present invention has several advantages over the prior art for making medicinally important compounds. The invention affords greater yields of styrylbenzoxazole products than prior methods. For example, Dryanska and Ivanov report a yield of 72-78% styrylbenzoxazole [Synthesis 37 (1976)]. They report even lower yields in phase transfer catalysis [Tetrah. Lett. 3519 (1975)]. Applicants report a yield of about 95% with the process of the present invention. Another advantage of the present invention is a process that readily affords aromatic aldehydes bearing protons. The novel process of the invention also provides a rapid entry into highly pure styrylbenzoxazoles, while circumventing problematic multistep sequences as required when butyllithium is used as the catalyst in condensation. In addition, the process of the new invention allows conditions which are amendable to large scale production, and obviates the need for additional steps to eliminate impurities. The invention is therefore a more economical, operationally practical, and efficient process for the construction of styrylbenzoxazoles than previous processes. The styrylbenzoxazole compounds useful as intermediates in the preparation of inhibitors of HIV reverse transcriptase. The invention may also provide a direct route to the synthesis of (aryloxy) alkylamines which possess gastric antisecretory activity and are thus useful as drugs in the treatment of ulcers.